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`Routes of Administration and Dosage Forms: Pharmacology Introduction: Merck Veterinary Manual
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`Pharmacology Introduction
`Routes of Administration and Dosage Forms
`
`A diverse range of dosage forms and delivery systems has been
`developed to provide for the care and welfare of animals. The
`development of dosage
`forms draws on
`the discipline of
`biopharmaceutics, which integrates an understanding of formulations,
`dissolution, stability, and controlled
`release
`(pharmaceutics);
`absorption, distribution, metabolism, and excretion (pharmacokinetics,
`PK); concentrationeffect relationships and drugreceptor interactions
`(pharmacodynamics, PD); and
`treatment of
`the disease state
`(therapeutics). Formulation of a dosage
`form
`typically
`involves
`combining an active ingredient and one or more excipients; the
`resultant dosage form determines the route of administration and the
`clinical efficacy and safety of the drug. Optimization of drug doses is
`also critical to achieving clinical efficacy and safety. Increasingly, a
`PK/PD model that describes the drug response is the basis of dose
`optimization. The PK and PD phases are linked by the premise that
`free drug in the systemic circulation is in equilibrium with the receptors.
`The PD phase generally involves interaction of the drug with a
`receptor, which triggers postreceptor events and eventually leads to a
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`drug effect (see Drug Concentration and Effect).
`
`Drug delivery strategies for veterinary formulations are complicated by
`the diversity of species and breeds treated, the wide range in body
`sizes, different husbandry practices, seasonal variations, cost
`constraints associated with the value of the animal being treated, the
`persistence of residues in food and fiber (see Chemical Residues in Food
`and Fiber), and the level of convenience, among other factors.
`Innovative solutions have been developed to meet many of these
`challenges (eg, the convenient dosing option offered by topical spoton
`formulations to treat external and internal parasites on dogs and cats,
`the microencapsulation of NSAIDs as a way to mask taste when these
`agents are added to the rations of horses). The anatomy of the GI tract
`of ruminants presents unique opportunities for controlledrelease drug
`delivery systems, and many such systems are on the market. For
`example, controlledrelease boluses have been developed to deliver
`antimicrobials, anthelmintics, production enhancers, nutritional
`supplements, and other drugs.
`
`ORAL ROUTE OF ADMINISTRATION AND DOSAGE FORMS
`The oral route of administration is frequently used in both companion
`and food animals. In dogs and cats, tablets, capsules, solutions, and
`suspensions are administered orally; pastes are also applied to the
`forelimbs of cats from which they are licked and ingested. In horses,
`solutions and suspensions are administered by nasogastric tubes,
`pastes are applied to the tongue, and granules are added to rations for
`ingestion. The oral route of administration is the most widely used in
`cattle, pigs, and poultry. Formulations range from premixes and
`drinking water additives to licks, pastes, drenches, tablets, capsules,
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`and boluses. Oral dosage forms are usually intended for systemic
`effects resulting from drug absorption from the GI tract; however, some
`oral suspensions, eg, kaolin, are intended to produce local effects, and
`these are not absorbed. Disadvantages of
`the oral route of
`administration
`include
`the relatively slow onset of action,
`the
`possibilities of irregular absorption, the destruction of acidlabile drugs
`in the stomach, and the unsuitability of this route for many high
`molecularweight drugs. Oral dosage
`forms
`require careful
`pharmaceutical formulation.
`
`(solutions, suspensions,
`liquids
`forms comprise
`Oral dosage
`emulsions, elixirs, and syrups), semisolids (pastes), and solids (tablets,
`capsules, powders, granules, premixes, and medicated blocks). These
`dosage forms together with examples of modifiedrelease delivery
`systems for ruminants are discussed below.
`
`A solution is a mixture of two or more components that form a single
`phase that is homogeneous down to the molecular level. Solutions
`offer several advantages over other dosage forms. Compared with
`solid dosage forms, solutions are absorbed faster and generally cause
`less irritation of the GI mucosa. Moreover, phase separation on
`storage is not a concern with solutions, as it may be for suspensions
`and emulsions. The disadvantages of solutions include susceptibility to
`microbial contamination and the hydrolysis in aqueous solution of
`susceptible active ingredients. In addition, the taste of some drugs is
`more unpleasant when in solution. A range of additives is used in the
`formulation of oral solutions, including buffers, flavors, antioxidants,
`and preservatives. Oral solutions provide a convenient means of drug
`administration to neonates and young animals.
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`A suspension is a coarse dispersion of insoluble drug particles,
`generally with a diameter >1 μm, in a liquid (usually aqueous) medium.
`Suspensions are useful to administer insoluble or poorly soluble drugs
`or when the presence of a finely divided form of the material in the
`GI tract is required. An example of the latter is the treatment of “frothy
`bloat” with dimethyl polysiloxanes, which relies on a dispersion of finely
`divided silica in the forestomach of ruminants. The taste of most drugs
`is less noticeable in suspension than in solution, because the drug is
`less soluble in suspension. Particle size is an important determinant of
`the dissolution rate and bioavailability of drugs in suspension. In
`addition to the excipients described above for solutions, suspensions
`include surfactants and thickening agents. Surfactants wet the solid
`particles, thereby ensuring the particles disperse readily throughout the
`liquid. Thickening agents reduce the rate at which particles settle to the
`bottom of the container. Some settling is acceptable, provided the
`sediment can be readily dispersed when the container is shaken.
`Redispersion of the suspension may not be achievable if the sediment
`has packed closely to form a hard mass, a process known as "caking."
`
`An emulsion is a system consisting of two immiscible liquid phases,
`one of which is dispersed throughout the other in the form of fine
`droplets; droplet diameter generally ranges from 0.1–100 μm. The two
`phases of an emulsion are known as the dispersed phase and the
`continuous phase. Emulsions are
`inherently unstable and are
`stabilized through the use of an emulsifying agent, which prevents
`coalescence of the dispersed droplets. Creaming, as occurs with milk,
`also occurs with pharmaceutical emulsions. However, it is not a
`serious problem because a uniform dispersion returns upon shaking.
`Creaming is, nonetheless, undesirable because it is associated with an
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`increased likelihood of the droplets coalescing and the emulsion
`“breaking.” Other additives
`include buffers, antioxidants, and
`preservatives. Emulsions for oral administration are usually oil (the
`active ingredient) in water, and they facilitate the administration of oily
`substances such as castor oil or liquid paraffin in a more palatable
`form.
`
`An elixir is a sweetened, usually hydroalcoholic solution of a bitter or
`nauseous drug intended for oral administration. The hydroalcoholic
`character of elixirs allows, within limits, both watersoluble and alcohol
`soluble medicinal substances to be maintained in solution. The
`proportion of alcohol in elixirs varies widely, a characteristic used to
`advantage to solubilize medicinal agents. If the active ingredient is
`sensitive to moisture, it may be formulated as a flavored powder or
`granulation and reconstituted
`in water
`immediately before oral
`administration. Nonmedicated elixirs are used as the vehicles for
`pharmaceutical formulations.
`
`A syrup is a concentrated aqueous solution of sugar or a sugar
`substitute with or without flavoring agents and a watersoluble drug.
`Sucrose is the most frequently used sugar, and syrups usually contain
`60%–80%. Syrups may also contain cosolvents, solubilizing agents,
`thickeners, or stabilizers. Nonmedicated syrups are used as vehicles
`for watersoluble drugs.
`
`A paste is a twocomponent semisolid in which drug is dispersed as a
`powder in an aqueous or fatty base. The particle size of the active
`ingredient in pastes can be as large as 100 μm. The vehicle containing
`the drug may be water; a polyhydroxy liquid such as glycerin,
`propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral
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`oil. Other formulation excipients include thickening agents, cosolvents,
`adsorbents, humectants, and preservatives. The thickening agent may
`be a naturally occurring material such as acacia or tragacanth, or a
`synthetic or chemically modified derivative such as xanthum gum or
`hydroxypropylmethyl cellulose. The degree of cohesiveness, plasticity,
`and syringeability of pastes is attributed to the thickening agent. It may
`be necessary to include a cosolvent to increase the solubility of the
`drug. Syneresis of pastes is a form of instability in which the solid and
`liquid components of the formulation separate over time; it is prevented
`by including an adsorbent such as microcrystalline cellulose. A
`humectant (eg, glycerin or propylene glycol) is used to prevent the
`paste that collects at the nozzle of the dispenser from forming a hard
`crust. Microbial growth in the formulation is inhibited using a
`preservative. It is critical that pastes have a pleasant taste or are
`tasteless and are able to be used throughout a wide temperature
`range. Pastes are a popular dosage form to treat cats and horses and
`can be easily and safely administered by owners.
`
`A tablet consists of one or more active ingredients and numerous
`excipients and may be a conventional tablet that is swallowed whole, a
`chewable tablet, or a modifiedrelease tablet (these are commonly
`referred to as modifiedrelease boluses when the unit size is large).
`Conventional and chewable tablets are used to administer drugs to
`dogs and cats, whereas modifiedrelease boluses are administered to
`cattle, sheep, and goats. The physical and chemical stability of tablets
`is generally better than that of liquid dosage forms. The main
`disadvantages of tablets are a relatively slow onset of action because
`of the need to pass into the intestine and then undergo disintegration
`and dissolution before absorption across the gut wall, the low
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`bioavailability of poorly watersoluble drugs or poorly absorbed drugs,
`and the local irritation of the GI mucosa that some drugs may cause.
`
`A capsule is an oral dosage form usually made from gelatin and filled
`with an active ingredient and excipients. Two common capsule types
`are available: hard gelatin capsules for solidfill formulations, and soft
`gelatin capsules for liquidfill or semisolidfill formulations. Soft gelatin
`capsules are suitable to formulate poorly watersoluble drugs because
`they afford good drug release and absorption by the GI tract. Gelatin
`capsules are frequently more expensive than tablets but have some
`advantages. For example, particle size is rarely altered during capsule
`manufacture, and capsules mask the taste and odor of the active
`ingredient and protect photolabile ingredients.
`
`A powder is a formulation in which a drug powder is mixed with other
`powdered excipients to produce a final product for oral administration.
`Powders have better chemical stability than liquids and dissolve faster
`than tablets or capsules because disintegration is not an issue. This
`translates into faster absorption for those drugs characterized by
`dissolution ratelimited absorption. Unpleasant tastes can be more
`pronounced with powders than with other dosage forms and can be a
`particular concern with infeed powders, leading to variable ingestion
`of the desired dose. Moreover, sick animals often eat less and are
`therefore not amenable to treatment with infeed powder formulations.
`Drug powders are principally used prophylactically
`in
`feed or
`formulated as a soluble powder for addition to drinking water or milk
`replacer. Powders have also been formulated with emulsifying agents
`to facilitate their administration as liquid drenches.
`
`A granule is a dosage form consisting of powder particles that have
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`been aggregated to form a larger mass, usually 2–4 mm in diameter.
`Granulation overcomes segregation of the different particle sizes
`during storage and/or dose administration, the latter being a potential
`source of inaccurate dosing. Granules and powders generally behave
`similarly; however, granules must deaggregate before dissolution and
`absorption.
`
`A premix is a solid dosage form in which an active ingredient, such as
`a coccidiostat, production enhancer, or nutritional supplement, is
`formulated with excipients. Premix products are mixed homogeneously
`with feed at rates (when expressed on an active ingredient basis) that
`range from a few milligrams to ~200 g/ton of feed. They are
`administered to poultry, pigs, and ruminants. The density, particle size,
`and geometry of the premix particles should match as closely as
`possible those of the feed in which the premix will be incorporated to
`facilitate uniform mixing. Issues such as instability, electrostatic
`charge, and hygroscopicity must also be addressed. The excipients
`present in premix formulations include carriers, liquid binders, diluents,
`anticaking agents, and antidust agents. Carriers, such as wheat
`middlings, soybean mill run, and rice hulls, bind active ingredients to
`their surfaces and are important in attaining uniform mixing of the
`active ingredient. A liquid binding agent, such as a vegetable oil,
`should be included in the formulation whenever a carrier is used.
`Diluents increase the bulk of premix formulations, but unlike carriers,
`they do not bind the active ingredients. Examples of diluents include
`ground limestone, dicalcium phosphate, dextrose, and kaolin. Caking
`in a premix formulation may be caused by hygroscopic ingredients and
`is addressed by adding small amounts of anti caking agents such as
`calcium silicate, silicon dioxide, and hydrophobic starch. The dust
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`associated with powdered premix formulations can have serious
`implications for both operator safety and economic losses and is
`reduced by including a vegetable oil or light mineral oil in the
`formulation. An alternative approach to overcoming dust is to granulate
`the premix formulation.
`
`A medicated block is a compressed feed material that contains an
`active ingredient, such as a drug, anthelmintic, surfactant (for bloat
`prevention), or a nutritional supplement, and is commonly packaged in
`a cardboard box to feed to livestock. Ruminants typically have free
`access to the medicated block over several days, and variable
`consumption may be problematic. This concern is addressed by
`ensuring the active ingredient is nontoxic, stable, palatable, and
`preferably of low solubility. In addition, excipients in the formulation
`modulate consumption by altering the palatability and/or the hardness
`of the medicated block. For example, molasses increases palatability,
`and sodium chloride decreases it. Additionally, the incorporation of a
`binder such as
`lignin sulfonate
`in blocks manufactured by
`compression, or magnesium oxide in blocks manufactured by chemical
`reaction, increases hardness. The hygroscopic nature of molasses in a
`formulation may also impact the hardness of medicated blocks and is
`addressed by using appropriate packaging.
`
`SYSTEMS
`
`ORAL MODIFIEDRELEASE DELIVERY
`RUMINANTS
`Several modifiedrelease delivery systems have been developed that
`take advantage of the unique anatomy of the ruminant forestomach.
`Prominent among these systems are intraruminal boluses, which
`contain a range of active ingredients including parasiticides, nutritional
`supplements, antibloat agents, and production enhancers. They are
`
`FOR
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`administered using a balling gun. Most of the commercially available
`intraruminal boluses are continuousrelease devices that rely on
`erosion, diffusion from a reservoir, dissolution of a dispersed matrix, or
`an osmotic “driver” to release the active ingredient. The payout period
`for intraruminal boluses is commonly >100 days. Regurgitation during
`rumination is prevented by the bolus having a density of ~3 g/cm3 or a
`variable geometry.
`
`Other types of oral modifiedrelease delivery systems are also
`available for ruminants. For example, sustainedrelease boluses that
`deliver sulfonamides throughout a period of ~72 hr are available to
`treat cattle.
`In addition, sustainedrelease boluses containing
`methoprene or diflubenzuron are approved for the control of manure
`breeding flies in cattle.
`
`The intraruminal devices to supplement ruminants with selenium,
`cobalt, or copper include soluble glass boluses and intraruminal
`pellets. Boluses of soluble glass containing selenium, cobalt, and
`copper are available
`for cattle and sheep. Because glass
`is
`susceptible to sudden changes in temperature, glass boluses should
`be at least 15°–20°C at the time of administration to avoid fracturing,
`which in turn may lead to regurgitation. Glass boluses are designed to
`dissolve in ruminal fluids, thereby releasing the incorporated elements.
`The composition of the glass determines the solubility of the bolus,
`with an increase in the ratio of monovalent to divalent cations resulting
`in an increase in solubility. The glass boluses are retained in the
`rumen for up to 9 mo.
`
`Intraruminal pellets containing selenium or cobalt are available for
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`sheep. Selenium or cobalt is released throughout a period of ~3 yr
`from the pellet matrix, which consists of compressed iron grit. When
`selenium or cobalt intraruminal pellets are administered alone, a
`“grinder” is usually coadministered to prevent the formation of calcium
`phosphate coatings on the surface of the pellets.
`
`Copper capsules, which contain oxidized copper wire particles
`encapsulated in gelatin, are available for adult sheep and goats. After
`oral administration, the gelatin capsule dissolves in the rumen and
`releases the particles of copper oxide. The particles progress to the
`abomasum, where some are trapped in the mucosal folds and release
`copper.
`
`PARENTERAL ROUTE OF ADMINISTRATION AND DOSAGE
`FORMS
`A drug given parenterally is one given by a route other than the mouth
`(topical dosage forms are considered separately). The three main
`parenteral routes of drug administration are IV, IM, and SC, and in all
`cases administration is usually via a hollow needle. Injectable
`preparations are usually sterile solutions or suspensions of drug in
`water or other suitable physiologically acceptable vehicles. Volumes
`delivered can range from milliliter to liter quantities. The time of onset
`of action for IV administration is seconds, and for IM and SC injections
`is minutes. Depot injectable preparations achieve prolonged release
`and maintain therapeutic concentrations of drug throughout 2–5 days.
`The bioavailability of a drug, particularly from prolongedrelease
`formulations, can be influenced by the location of the IM injection site.
`SC implants and pellets also achieve prolonged release of drug. A
`number of recombinant proteins and peptides are orally inactive and
`must be given by the parenteral route. Specialized dosage forms,
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`usually for parenteral administration, are required for vaccines. In food
`animals,
`intramammary
`infusions and
`intravaginal devices are
`administered by the parenteral route.
`
`Parenteral dosage forms and delivery systems include injectables (ie,
`solutions, suspensions, emulsions, and dry powders for reconstitution),
`intramammary infusions, intravaginal delivery systems, and implants.
`These dosage forms and delivery systems as well as the special
`considerations
`relating
`to
`intraarticular
`injections,
`recombinant
`proteins and peptides, and vaccines are discussed below.
`
`A solution for injection is a mixture of two or more components that
`form a single phase that is homogeneous down to the molecular level.
`“Water for injection” is the most widely used solvent for parenteral
`formulations. However, a nonaqueous solvent or a mixed
`aqueous/nonaqueous solvent system may be necessary to stabilize
`drugs that are readily hydrolyzed by water or to improve solubility. A
`range of excipients may be included in parenteral solutions, including
`antioxidants, antimicrobial agents, buffers, chelating agents, inert
`gases, and substances to adjust tonicity. Antioxidants maintain product
`stability by being preferentially oxidized over the shelf life of the
`product. Antimicrobial preservatives inhibit the growth of any microbes
`accidentally introduced when doses are being withdrawn from multiple
`dose bottles, and they act as adjuncts in aseptic processing of
`products. Buffers are necessary to maintain both solubility of the active
`ingredient and stability of the product. Chelating agents are added to
`complex and thereby inactivate metals, including copper, iron, and
`zinc, which generally catalyze oxidative degradation of drugs. Inert
`gases are used to displace the air in solutions and enhance product
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`integrity of oxygensensitive drugs. Isotonicity of the formulation is
`achieved by including a tonicityadjusting agent. Failing to adjust the
`tonicity of the solution can result in the hemolysis or crenation of
`erythrocytes when hypotonic or hypertonic solutions, respectively, are
`given IV in quantities >100 mL. Injectable formulations must be sterile
`and free of pyrogens. Pyrogenic substances are primarily lipid
`polysaccharides derived from microorganisms, with those produced by
`gramnegative bacilli generally being most potent. Injectable solutions
`are very commonly used, and aqueous solutions given IM result in
`immediate drug absorption, provided precipitation at the injection site
`does not occur.
`
`A suspension for injection consists of insoluble solid particles
`dispersed in a liquid medium, with the solid particles accounting for
`0.5%–30% of the suspension. The vehicle may be aqueous, oil, or
`both. Caking of injectable suspensions is minimized through the
`production of flocculated systems, comprising clusters of particles
`(flocs) held together in a loose, open structure. Excipients in injectable
`suspensions
`include
`antimicrobial
`preservatives,
`surfactants,
`dispersing or suspending agents, and buffers. Surfactants wet the
`suspended powders and provide acceptable syringeability while
`suspending agents modify the viscosity of the formulation. The ease of
`injection and the availability of the drug in depot therapy are affected
`by the viscosity of the suspension and the particle size of the
`suspended drug. These systems afford enhanced stability to active
`ingredients
`that are prone
`to hydrolysis
`in aqueous solutions.
`Injectable suspensions are commonly used. Compared with that of
`injectable solutions,
`the rate of drug absorption of
`injectable
`suspensions is prolonged because additional time is required for
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`disintegration and dissolution of the suspended drug particles. The
`slower release of drug from an oily suspension compared with that of
`an aqueous suspension is attributed to the additional time taken by
`drug particles suspended in an oil depot to reach the oil/water
`boundary and become wetted before dissolving in tissue fluids.
`
`An emulsion for injection is a heterogeneous dispersion of one
`immiscible liquid in another; it relies on an emulsifying agent for
`stability. Parenteral emulsions are rare, because
`it
`is seldom
`necessary to achieve an emulsion for drug administration. Untoward
`physiologic effects after IV administration may occur, including emboli
`in blood vessels if the droplets are >1 μm in diameter. Formulation
`options for injectable emulsions are also severely restricted, because
`suitable stabilizers and emulsifiers are very limited. Examples of
`parenteral emulsions include oilinwater, sustainedrelease depot
`preparations (given IM), and waterinoil emulsions of allergenic
`extracts (given SC).
`
`A dry powder for parenteral administration is reconstituted as a
`solution or as a suspension immediately before injection. The principal
`advantage of this dosage form is that it overcomes the problem of
`instability in solution. Proteins and other materials that are extremely
`heat sensitive cannot be dried in pharmaceutical driers. Rather, freeze
`drying, or lyophilization, is used to produce a porous powder that
`reconstitutes readily.
`
`Intramammary infusion products to treat mastitis are available for
`lactating and nonlactating (dry) cows. Lactating cow intramammary
`infusions should demonstrate fast and even distribution of the drug
`and a low degree of binding to udder tissue. These properties result in
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`Routes of Administration and Dosage Forms: Pharmacology Introduction: Merck Veterinary Manual
`lower concentrations of drug residues in the milk. In contrast, it is
`desirable for nonlactating cow formulations to demonstrate prolonged
`drug release and a high degree of binding to mammary secretions and
`udder tissues. Particle size is particularly important, because it affects
`both the rate of release of the active ingredient and irritancy to the
`udder
`tissue. Drug particle size
`in nonlactating
`intramammary
`formulations is usually smaller than in those for lactating cows, which
`is critical to reduce irritancy during prolonged retention in the udder.
`Thickening agents are added to modify the rate of release of the
`suspended particles from oil formulations, and antioxidants are
`commonly incorporated to prevent rancidity. Mastitis infusion products
`are often terminally sterilized by irradiation.
`
`Intravaginal delivery systems include controlled internal drug
`release (CIDR) devices, progesteronereleasing intravaginal devices
`(PRIDs), and vaginal sponges. These systems are used for estrus
`synchronization in sheep, goats, and cattle. Silicone is used in the
`manufacture of the Tshaped CIDR device and the coilshaped PRID,
`whereas intravaginal sponges are made from polyurethane. The active
`ingredients in these systems are synthetic or natural hormones such
`as progesterone, methylacetoxy progesterone, fluorogestone acetate,
`or estradiol benzoate. An applicator consisting of a speculum and a
`separate plunger is used to insert sponges into the vaginal cavities of
`sheep and goats, and PRIDs into the vaginal cavities of cattle. A
`different type of applicator is used to insert CIDR devices into the
`vaginal cavities of sheep, goats, and cattle. Retention in the vagina
`depends on either the wings (CIDR device) or the entire device
`(sponges and PRIDs) expanding. With all three devices, gentle
`pressure is exerted on the vaginal wall. Retention of the device is
`
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